Early Histone Deacetylase Inhibition Mitigates Ischemia/Reperfusion Brain Injury by Reducing Microglia Activation and Modulating Their Phenotype

Hell, this was already researched in June 2007 and June 2013 and nothing seems to have been done with human testing. NO STROKE LEADERSHIP AND NO STROKE STRATEGY causes failures like this. 

Histone Deacetylase Inhibitors Exhibit Anti-Inflammatory and Neuroprotective Effects in a Rat Permanent Ischemic Model of Stroke: Multiple Mechanisms of Action June 2007

  

Histone deacetylase inhibitors are neuroprotective and preserve NGF-mediated cell survival following traumatic brain injury June 2013

 The latest here:

Early Histone Deacetylase Inhibition Mitigates Ischemia/Reperfusion Brain Injury by Reducing Microglia Activation and Modulating Their Phenotype

Shuyuan Li^1†, Xiaoshuang Lu^1†, Qian Shao², Zixin Chen¹, Qiong Huang¹, Zinan Jiao¹, Xiaodi Huang¹, Maosong Yue¹, Jingwen Peng², Xin Zhou¹, Dachong Chao¹, Heng Zhao³, Juling Ji⁴, Yuhua Ji^1,2* and Qiuhong Ji^3*

• ¹College of Life Science and Technology, Institute of Immunology, Jinan University, Guangzhou, China
• ²Key Laboratory of Neuroregeneration, Nantong University, Nantong, China
• ³Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
• ⁴Department of Pathology, Medical School of Nantong University, Nantong, China

Histone deacetylase inhibitors (HDACi) are a promising therapeutic intervention for stroke. The involvement of the anti-inflammatory effects of HDACi in their neuroprotection has been reported, but the underlying mechanisms are still uncertain. Given the post-stroke inflammation is a time-dependent process, starting with acute and intense inflammation, and followed by a prolonged and mild one, we proposed whether target the early inflammatory response could achieve the neuroprotection of HDACi? To test this hypothesis, a single dose of suberoylanilide hydroxamic acid (SAHA) (50 mg/kg), a pan HDACi, was intraperitoneally (i.p.) injected immediately or 12 h after ischemia onset in a transient middle cerebral artery occlusion (tMCAO) mouse model. Compared with delayed injection, immediate SAHA treatment provided more protection, evidenced by smaller infarction volume, and a better outcome. This protection was accompanied by suppression of pro-inflammatory cytokines and reduction of activated microglia in the early stage of post-stroke inflammation. Moreover, SAHA treatment suppressed M1 cytokine expression (IL-6, TNF-α, and iNOS) while promoted the transcription of M2 cytokines (Arg-1 and IL-10) in LPS-challenged mouse microglia, and enhanced CD206 (M2 marker) but decreased CD86 (M1 markers) levels in microglia isolated from the ipsilateral hemisphere of MCAO mice. Collectively, our data suggested that the protection of SAHA on ischemic brain injury was closely associated with its inhibition on the early inflammatory response, and this inhibition was related to its reducing microglia activation and priming the activated microglia toward a more protective phenotype.

Introduction

Ischemic stroke is a leading cause of death and adult disability worldwide (1); aside from tissue plasminogen activator (tPA), available treatments are minimal (2, 3). Protein acetylation modulated by histone acetyltransferases (HAT) and histone deacetylases (HDAC) is a widespread posttranslational modification (4, 5). In the past decade, multiple studies highlighted protein acetylation is essential for maintaining the homeostasis of the central nervous system, and its balance is frequently disrupted under disease and injury states, including stroke, and multiple neurodegenerative disorders (6, 7). Interestingly, accumulating in vivo and in vitro evidence proved modulation of protein acetylation by HDACi could mitigate ischemia-induced brain damage and promote endogenous regeneration and recovery (8, 9). They are therefore considered a promising therapeutic intervention for stroke and a variety of neurodegenerative diseases. Post-ischemic inflammation is a hallmark of ischemic stroke pathology, which plays critical roles in acute brain damage and profoundly affects long-term recovery (10, 11). Notably, it is a time-dependent process, starting with acute and intense inflammation and followed by a prolonged and mild one (12, 13). Microglia, the resident macrophages of the brain, and macrophages derived from infiltrated peripheral monocytes/macrophages are the two main elements participating in this immune response (14). These are two ontogenetically distinct cell populations and are activated or recruited with distinct kinetics after the onset of ischemia (14, 15).

Moreover, the roles of microglia and macrophages in the post-stroke inflammatory response are further complicated by their plasticity, as both of them can adopt different phenotypes in response to different extracellular milieu (16, 17). The two well-characterized are the “classically activated” M1 phenotype and the “alternatively activated” M2 phenotype. Generally, classically activated microglia/macrophages exert cytotoxic effects by releasing pro-inflammatory factors, which exacerbate brain infarction and damage (18). In contrast, alternatively activated microglia/macrophages exhibit an anti-inflammatory phenotype and promote brain recovery by clearing cell debris and releasing some anti-inflammatory cytokines and trophic factors. Accordingly, modulating the balance between the pro- and anti-inflammatory phenotypes represent a novel and promising strategy for stroke treatment (19).

To date, several studies reported the involvement of the anti-inflammatory effects of HDACi in their neuroprotection in acute brain ischemia (20, 21). In these studies, the long-term treatment of HDACi with multi-injection strategy was adopted. However, given the time-dependent inflammatory response of stroke (10) and the multipotency of HDACi (22), this long-term treatment is hard to figure out the mechanism underlying the anti-inflammatory effects of HDACi. Here, we proposed whether targeting the acute and intense early inflammatory responses by HDACi could achieve a protective effect on acute brain ischemia? More importantly, this single administration strategy could help us to understand the cellular mechanisms underlying the neuroprotection of HDACi.

To test the hypothesis, we compared the protection of a single dose of SAHA, an FDA-approved pan-HDACi, administrated at early and late time points in a tMCAO mouse model. Then, the anti-inflammatory effects of SAHA were determined by its impact on the expression of inflammatory cytokine, as well as microglia activation and the infiltration of peripheral monocytes. Finally, the impact of SAHA on microglia polarization was examined in vitro and in vivo. Our data showed the better protection of early SAHA treatment and suggested this protection was closely associated with its anti-inflammatory effect in the early stage of brain ischemia. Moreover, its anti-inflammatory effect was closely related to its reducing microglia activation and priming the activated microglia toward a more protective phenotype.